Process for producing sulfone containing thiophenols

ABSTRACT

A method for the preparation of aromatic thiols which comprises reacting a benzenoid compound having at least one halogen atom activated by an inert electron-attracting group with an alkali metal disulphide in stoichiometric proportion of from 1.0 to 2.0 moles per gram atom of activated halogen to be replaced.

This invention relates to organic thiols and in particular to aromaticthiols.

According to the present invention, a method is provided for thepreparation of aromatic thiols which comprises reacting a benzenoidcompound having at least one halogen atom activated by an inertelectron-attracting group with an alkali metal disulphide instoichiometric proportion of from 1.0 to 2.0 moles per gram atom ofactivated halogen to be replaced.

Any benzenoid compound having at least one halogen atom activated by atleast one electron withdrawing group in at least one of the positionsortho or para to a halogen atom may be used in the process of theinvention. Any electron withdrawing group may be used provided that itis inert to the reaction. More powerful electron withdrawing groups arepreferred and preferably the aromatic ring containing the halogen atomto be replaced should not be substituted with any electron-donatinggroups, in any of the positions ortho or para to the halogenatom.

The activating group may be either a univalent group that activate oneor more halogens on the same ring, e.g. a nitro group, phenylsulphone,or alkylsulphone, cyano, trifluoromethyl, nitroso, and hetero nitrogenas in pyridine, or a bivalent group which can activate displacement ofhalogen(s) on one (or two) rings, e.g. sulphone group (--SO₂ --);carbonyl group (--CO--); vinyl group (--CH=CH--); sulphoxide group(--SO--); azo-group (--N=N--); saturated fluorocarbon group (--CF₂ CF₂--); organic phosphine oxides [--PO(R)--]; where R is a hydrocarbongroup, and the ethylidene group [--C(CX₂)--] where X can be hydrogen orhalogen or which can activate halogens on the same ring such as withdifluorobenzoquinone, 1,4- or 1,5- or 1,8-difluoroanthraquinone.

Examples of compounds containing a univalent activating group are:##SPC1##

And of compounds containing a bivalent activating group are ##SPC2##

Where X is a halogen atom.

The halogen atoms, X, are preferably chlorine atoms or bromine atoms.Bromine derivatives are relatively expensive although they resemblechlorine derivatives in performance. Iodine derivatives may also be usedbut fluorine derivatives are generally less suitable.

The alkali metal disulphide has essentially the molecular formula M₂ S₂where M is an alkali metal. Some or all of the alkali metal cation inthe reagent may be replaced by an organic onium cation having apositively charged heteroatom (for example a quaternary ammonium cationsuch as tetramethylammonium) stable under the conditions of thereaction, and the term "alkali metal salt" as used herein is deemed torefer also to salts containing such onium cations. Preferably the alkalimetal cation is sodium or potassium ammonium. The disulphide isconveniently prepared by reacting approximately a given gram atom ofsulphur with the same moles of alkali metal sulphide.

The reaction of the invention is desirably carried out in the presenceof a solvent which is preferably an alcohol, a glycol, or a glycolmonoether, of which ethylene glycol is particularly preferred.

As with most chemical reactions, a compromise has to be reached betweenobtaining essentially a single product by performing the reaction atambient temperature over a long period of time or carrying out thereaction at higher temperatures over a shorter reaction time withattendant risk of a multiplicity of products and product degradation.The reaction of the present invention may be carried out at temperaturesbetween ambient and 200°C, preferably between 100° and 140°C.

The reaction is also carried out preferably in an inert atmosphere, e.g.nitrogen, so as to reduce the risk of oxidation of the thiol group andattendant risk of polymerisation.

In accordance with the method of the present invention, from 1.0 to 2.0(preferably 1.3 to 1.7) moles of alkali metal disulphide are present foreach gram atom of halogen to be replaced in the benzenoid compound ifthe yield of aromatic thiol is to be optimised. Hence if 1 mole of adihalogenated benzenoid compound (in which both halogen atoms areactivated) is reacted with 3 moles of alkali metal disulphide, 1 mole ofbisthiol will be produced; if 1 mole of a dihalo benzenoid compound isreacted with about 1.5 moles of alkali metal disulphide, then 1 mole ofthe halothiol of the benzenoid compound will be formed.

The thiol is conveniently extracted from the reaction mixture byacidification followed by filtration, washing of the precipitate anddrying, preferably in an atmosphere of nitrogen at temperatures lessthan 80°C so as to minimise the risk of oxidation.

In a preferred embodiment of the method of the invention the crudeprecipitated thiol is extracted into an aqueous solution of an alkalimetal sulphite and the solution filtered. The filtrate is then acidifiedto a pH of greater than 5 conveniently with mineral acid (e.g.hydrochloric acid) to precipitate thiol which can be filtered, washedand dried as described hereinbefore. The precipitate from the sulphiteextraction is treated with warm aqueous alkali metal sulphide solutionand the resulting solution filtered. This filtrate is acidified to aboutpH 1 with mineral acid to precipitate further quantities of crude thiolwhich can be filtered off and extracted into aqueous solution of alkalimetal sulphite as before.

The thiols of the invention may be used in the preparation ofpharmaceutical products and in particular bisthiols may be used in thepreparation of polymeric materials such as for example those describedin U.S. Pat. No. 3,432,468, German Pat. No. 1,938,806 and NetherlandsPat. No. 6,903,070 and halothiols by a method similar to that describedin British patent specifications 1,153,035 and 1,177,183.

The invention is illustrated by the following examples.

EXAMPLE 1

Sodium sulphide nonahydrate (Na₂ S.9H₂ O; 864.7 g; 3.6 moles) andelemental sulphur (115.2 g; 3.6 g atoms) were dissolved in ethyleneglycol (1800 cm³) in a roundbottomed flask fitted with a stirrer,condenser, and nitrogen inlet. Bis-(4-chlorophenyl)sulphone (344.6 g;1.2 moles) were added and the mixture stirred and heated at 130°C for 20hours under an atmosphere of nitrogen. The dichloride had completelydissolved after 2.5 hours.

The dark brown reaction mixture was cooled, diluted with water (5 dm³)and the solution was acidified to pH 1 with hydrochloric acid. The paleyellow precipitate was filtered off and washed well with water.

The precipitate was digested for 3 hours at 90°-100°C with a solutioncontaining sodium sulphite heptahydrate (Na₂ SO₃.7H₂ O; 1815.8 g; 7.2moles) in 3 dm³ of water. The mixture was allowed to cool to roomtemperature and the insoluble material filtered off and washed withwater. The pale yellow aqueous sulphite extract and washings wereacidified, with stirring, to pH 5.5 with hydrochloric acid, and thewhite granular product, bis-(4-mercaptophenyl) sulphone (89 g) wasfiltered off, washed with water, and dried at 70°C under nitrogen.

The sulphite insoluble material was dissolved in 2 liters of aqueoussodium sulphide solution (2 dm³ containing 350 g of Na₂ S.9H₂ O) at60°C. The solution was filtered to remove impurities, and acidified topH 1. The precipitate was filtered off, washed with water and digestedwith aqueous sodium sulphite solution (containing 400 g of Na₂ SO₃.7H₂O) as described above. A further 54 g of bis-(4-mercaptophenyl) sulphonewere isolated by acidifying the sulphite extract.

The procedure of dissolving the sulphite-insoluble material in aqueoussulphide solution, acidifying, and digesting with aqueous sulphitesolution, was repeated twice - i.e. four separate crops ofbis-(4-mercaptophenyl) sulphone were obtained. For the third cycle, 250g of sulphide and 300 g of sulphite were used, and for the fourth, 150 gof sulphide and 200 g of sulphite. The third and fourth cycle yields ofbis-(4-mercaptophenyl) sulphone were 62 g and 32 g respectively.

The total yield of bis-(4-mercaptophenyl)sulphone was 237 g (70% basedon bis-(4-chlorophenyl)sulphone and had melting point of 138°-140°C.

EXAMPLE 2

A series of experiments were carried out according to the procedure ofExample 1, using varying amounts of sodium disulphide, in order todetermine the optimum ratio of moles of disulphide per g atom ofchlorine. The results in Table 1 show the % yield ofbis-(4-mercaptophenyl)sulphone after a standard wash with sodiumsulphite solution as described in Example 1. (i.e. % yield after 1stcycle).

                  TABLE 1                                                         ______________________________________                                        Moles of disulphide                                                                            % yield of                                                   per g.atom chlorine                                                                            bis-(4-mercaptophenyl)                                                        sulphone                                                     ______________________________________                                        0.33             4                                                            1.0              23                                                           1.5              30                                                           2.0              20                                                           ______________________________________                                    

These results are presented in FIG. 1 and show that the optimum yield ofbis-(4-mercaptophenyl)sulphone is obtained when 1.5 moles of disulphideper g atom of chlorine are used.

EXAMPLE 3

Sodium sulphide (60%; Na₂ S.3H₂ O; 465 g; 3.58 mole) and elementalsulphur (114.6 g; 3.58 mole) were dissolved in ethylene glycol (2400cm³) in a round-bottomed flask equipped with a stirrer, condenser, andnitrogen inlet. Bis-(4-chlorophenyl)ketone (300 g; 1.19 mole) was addedand the mixture stirred and heated at 130°C for 4 hours.

The dark brown reaction mixture was cooled, diluted with water(6 dm³)and the solution acidified to pH 1 with hydrochloric acid. The paleyellow precipitate was filtered off and washed well with water.

The precipitate was digested for 2 hours at 80°C with a solutioncontaining sodium sulphite heptahydrate (Na₂ SO₃.7H₂ O; 1804 g; 7.16mole) in 3 dm³ of water. The mixture was allowed to cool to roomtemperature and the insoluble material filtered off and washed withwater. The yellow aqueous sulphite extract and washings were acidified,with stirring to pH 5.5 with hydrochloric acid, and the pale yellowgranular product, bis-(4-mercaptophenyl) ketone (80 g) was filtered off,washed with water, and dried at 70°C under vacuum.

The sulphite insoluble material was dissolved in aqueous sodium sulphidesolution (2 dm³ containing 400 g; 3.1 mole of 60% Na₂ S) at 60°C. Thesolution was filtered to remove impurities and acidified to pH 1. Theprecipitate was filtered off, washed with water and digested withaqueous sodium sulphite solution (1562 g; 6.2 mole of Na₂ SO₃.7H₂ O) asdescribed above. A further 70 g of bis-(4-mercaptophenyl)ketone wasisolated by acidifying the sulphite extract.

The procedure of dissolving the sulphite-insoluble material in aqueoussulphide solution, acidifying, and digesting with aqueous sulphitesolution, was repeated twice -- i.e. four separate crops were obtained.

Table 2 illustrates the yields of bis-thiol obtained in each cycletogether with amount of reagent.

                  TABLE 2                                                         ______________________________________                                                 Na.sub.2 S Na.sub.2 SO.sub.3                                                                           Bis-                                                                          thiol                                       ______________________________________                                        Reaction mixture                                                                         465 g (3.58 mole)                                                                          1804 g (7.16 mole)                                                                          80 g                                    1st Cycle  400 g (3.1  mole)                                                                          1562 g (6.2  mole)                                                                          70 g                                    2nd Cycle  280 g (2.15 mole)                                                                          1084 g (4.3  mole)                                                                          40 g                                    3rd Cycle  180 g (1.38 mole)                                                                           700 g (2.7  mole)                                                                          20 g                                    ______________________________________                                    

The total yield of bis-(4-mercaptophenyl)ketone was 237 g [70% based onbis-(4-chlorophenyl)ketone] and the product on recrystallisation fromethanol had a melting point 176°-177°C.

EXAMPLE 4

Sodium sulphide (60% Na₂ S; 26.0 g; 0.2 mole) and elemental sulphur (6.4g; 0.2 mole) were dissolved in ethylene glycol (300 cm³) in around-bottomed flask equipped with a stirrer, condenser and nitrogeninlet. Bis-(4-chlorophenyl)ketone (65.2 g; 0.26 mole) was added and themixture stirred and heated at 120°C for 4 hours under a nitrogenatmosphere.

The reaction mixture was cooled and the precipitated solid (unreactedbis-(4-chlorophenyl)ketone; 35 g) filtered off. The filtrate was dilutedwith water and acidified with hydrochloric acid. The precipitate wasfiltered off, washed with water and digested with aqueous sodiumsulphite heptahydrate (Na₂ SO₃.7H₂ O; 100 g; 0.4 mole) at 80°C for onehour. The solid was filtered off and washed with water. The sulphiteinsoluble material was treated with aqueous sodium hydroxide solution(30 g; 0.85 mole in 200 cm³ of water) at 60°C for two hours. The cooledsodium hydroxide extract was filtered and the filtrate acidified withhydrochloric acid. The white precipitate was filtered off, washed withwater and recrystallised from degassed ethanol and found to haveinfra-red and nuclear magnetic resonance spectra consistent with itsbeing 4-chloro-4'mercaptobenzophenone. ##SPC3##

The yield of 4-chloro-4'-mercaptobenzophenone was 20 g [67% based on30.2 g of bis-(4-chlorophenyl)sulphone].

EXAMPLE 5

A solution of sodium sulphide nonahydrate (35 g; 0.144 mole) and sulphur(4.69 g; 0.146 mole) in a mixture of water (100 cm³) and sulpholane (50cm³) was slowly added to a stirred solution at less than 120°C of4,4'-dichlorodiphenyl sulphone (28.7 g; 0.100 mole) in sulpholane (75cm³), contained in a round-bottom flask fitted with a nitrogen inlet, astill head and a stirrer. The resulting solution was stirred for 2 hoursunder reflux. A solution of sodium hydroxide (8.0 g; 0.20 mole) in amixture of water (50 cm³) and sulpholane (50 cm³) was added slowly tothe reaction mixture which was stirred at 120°C for a further 2 hours.The resulting solution was cooled, poured on to ice and the clearsolution obtained was acidified with concentrated hydrochloric acid. Asolid precipitated which was extracted with two portions (ca. 250 cm³)of aqueous potassium hydroxide solution (4N). The combined alkalineextracts were acidified with concentrated hydrochloric acid and theprecipitate was extracted into chloroform. The chloroform solution wasdried over sodium sulphate and evaporated to yield a residue whosenuclear magnetic resonance, infra-red and mass spectra were consistentwith the structure ##SPC4##

We claim:
 1. A method for the preparation of aromatic thiols whichcomprises reacting in an inert solvent the corresponding aromatic halidehaving the halogen atom activated by an inert electron-attracting groupattached to the same aromatic ring as the halogen atom and ortho or parathereto, wherein said electron-attracting group is --SO₂ --, with analkali metal disulphide in stoichiometric proportion of from 1.0 to 2.0moles per gram atom of activated halogen to be replaced and thenacidifying the reaction mixture.
 2. A method according to claim 1 inwhich the alkali metal disulphide is present in stoichiometricproportion of from 1.3 to 1.7 moles per gram atom of activated halogento be replaced.
 3. A method according to claim 1 in which the aromaticthiol is extracted from the acidified reaction mixture which comprisesfiltering off precipitated crude thiol, digesting the crude thiol withan aqueous solution of alkali metal sulphite, filtering, and acidifyingthe filtered alkali metal sulphite solution to a pH of not less than 5to thereby precipitate the thiol.
 4. A method according to claim 3,which includes the further steps of digesting the solid residue obtainedon filtering the alkali metal sulphite solution with an aqueous alkalimetal sulphide solution to form a solution, acidifying this solution toprecipitate a further quantity of crude thiol and then digesting thisfurther quantity of crude thiol with an aqueous solution of an alkalimetal sulphite, filtering, and acidifying the filtered alkali metalsulphite solution to a pH of not less than 5, thereby precipitating afurther quantity of the thiol.
 5. The process of claim 1 wherein thearomatic halide is bis-(4-chlorophenyl)sulphone and the thiol product isbis-(4-mercaptophenyl)sulphone.
 6. The process of claim 1 wherein thearomatic halide is 4,4'-dichlorodiphenyl sulphone and the thiol productis 4-chloro-4'-mercaptophenyl sulphone.
 7. Bis-(4-mercaptophenyl)ketone.
 8. 4-Chloro-4'-mercaptobenzophenone. 9.4-Chloro-4'-mercaptophenylsulphone.
 10. A method according to claim 1 inwhich the aromatic halide has two activated halogen atoms.